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Zuclopenthixol versus placebo for people with schizophrenia

People with schizophrenia often hear voices and see things (hallucinations) and have strange beliefs (delusions). The main treatment for these symptoms of schizophrenia is antipsychotic drugs. Zuclopenthixol is an older antipsychotic drug, first introduced in 1962, that has three distinct formulations zuclopenthixol dihydrochloride, zuclopenthixol acetate (or Acuphase), and zuclopenthixol decanoate. Although zuclopenthixol has been in common use for many years, no previous systematic review of its effectiveness compared to placebo (‘dummy’ treatment) in schizophrenia has been undertaken. Given the widespread use of this drug, it is important to look at the effectiveness of all three formulations of this commonly-used drug so that health professionals, policy makers and people with schizophrenia can make better-informed choices.

We searched for randomised controlled trials comparing zuclopenthixol with placebo in 2013. We found only two studies with 65 participants which could be included in this review. Overall the quality of these studies was low, with small numbers of people and significant bias. The studies were old, from 1968 and 1972, and would be unlikely to pass modern peer review standards. Only short-term information and data could be found, and only about zuclopenthixol dihydrochloride.

The information is very limited but suggests that zuclopenthixol can lead to improvement in global state in comparison with placebo. However, there is also increased risk of side effects such as sedation,and tiredness.

Given the low quality of information and age of the two studies, further research is needed, particularly further research on zuclopenthixol compared to newer and more recent antipsychotic drugs.

Authors' conclusions:

For people with schizophrenia this review shows that zuclopenthixol dihydrochloride may help with the symptoms of schizophrenia. The review provides some trial evidence that, if taking zuclopenthixol dihydrochloride, people may experience some adverse effects and sedation compared with placebo. However this evidence is of very low quality and with some significant sources of bias. There are no data for zuclopenthixol decanoate or zuclopenthixol acetate.

For clinicians, the available trialdata on the absolute effectiveness of zuclopenthixol dihydrochloride do support its use but the limited nature of the data and significant sources of bias make conclusions hard to draw. Zuclopenthixol in all three forms is a commonly used antipsychotic and it is disappointing that there are so few data regarding its use.

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Background:

Zuclopenthixol is an older antipsychotic that has three distinct formulations (zuclopenthixol dihydrochloride, zuclopenthixol acetate or Acuphase and zuclopenthixol decanoate). Although it has been in common use for many years no previous systematic review of its efficacy compared to placebo in schizophrenia has been undertaken.

Objectives:

To evaluate the effectiveness of all formulations of zuclopenthixol when compared with a placebo in schizophrenia.

Search strategy:

On 6 November 2013 and 20 October 2015, we searched the Cochrane Schizophrenia Group Trials Register, which is based on regular searches of MEDLINE, EMBASE, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and registries of clinical trials. We also checked the references of all included studies and contacted authors of included studies for relevant studies and data.

Selection criteria:

We included all randomised controlled trials comparing zuclopenthixol of any form with placebo for treatment of schizophrenia or schizophrenia-like psychoses.

Data collection and analysis:

We extracted and cross-checked data independently. We identified only a small number of studies so we cross checked all studies. We calculated fixed-effect relative risks (RR) and 95% confidence intervals (CI) for dichotomousdata. We analysed by intention-to-treat. Where possible we converted continuous outcomes into dichotomous outcomes. When this was not possible we used mean differences (MD) for continuous variables. We assessed risk of bias for included studies and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to create a 'Summary of findings' table.

Main results:

Only two studies, with a total of 65 participants, were eligible for inclusion in the review. Overall the quality of the two studies was low, with small study populations and significant sources of bias, so we were not able to use all the data in our comparisons. . The studies were old from 1968 and 1972, and would be unlikely to pass modern peer review standard. We were only able to find short-term data and only trials randomising zuclopenthixol dihydrochloride. We also hoped to identify data for zuclopenthixol acetate versus placebo and zuclopenthixol decanoate versus placebo comparisons. We were unable to identify any studies that included data on these two fairly widely used drugs.

For our primary outcome of interest, clinically significant improvement, we found one study that provided useable data. Global state measured by clinical global impression scale (CGI) improvement showed different ratings when assessed by a psychiatrist or a nurse.The psychiatrist scores failed to achieve statistical significance, however when assessed by nursing staff, the difference favouring zuclopenthixol did reach statistical significance (1 RCT n = 29, RR 2.57 95% CI 1.06 to 6.20, very low quality data). There was also evidence of increased sedation with those treated with zuclopenthixol when compared with placebo (1 RCT n = 29, RR 4.67 95% CI 1.23 to 17.68, very low quality data). 'Leaving the study early' data were equivocal. No useable data were available for outcomes such as relapse, mental state, death, quality of life, service use or economic costs.

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